“Falling off” / “Dropping off” Defined as pathway of cell death that is induced by a tightly regulated suicide program in which cells destined to die activate enzymes capable of degrading the cells own nuclear DNA and nuclear and cytoplasmic proteins
CAUSES OF APOPTOSIS: Physiologic conditions include:1. During embryogenesis2. Hormone-dependent involution3. Cell deletion in intestinal crypt epithelium4. Involution of thymus5. Deletion of autoreactive T cells in thymus6. Cell death by CTLs (viruses, tumor cells, transplant rejection)
Pathologic conditions include:1. DNA damage e.g. Hypoxia Radiation Cytotoxic anticancer drugs2 . Pathologic atrophy in parenchymal organs after duct obstruction
Morphology: Light Microscopy (H & E): ◦ Seen in single cells or clusters of cells ◦ Cells appear as round or oval masses ◦ Cell shrinkage – intensely eosinophilic cytoplasm
◦ Nuclear C hromatin condenses◦ Karyorrhexis◦ Apoptotic bodies form◦ Phagocytosis of apoptotic bodies◦ No inflammatory response
Mechanisms of Apoptosis:1. Signaling i.e. ‘death signals’ or ‘survival signals’2. Control & Regulation By specific proteins (‘inhibits’ or ‘promotes’ apoptosis) & Activation of caspases 2 pathwaysi. Mitochondrial pathwayii. Death receptor pathway
3. Execution By specific executioner caspases Their functions include:i. Protein cleavage (cytoskeletal & nuclear proteins)ii. DNA breakdown (by cytoplasmic DNase activation)4. Removal of apoptotic cells
Dysregulated apoptosis (“too little” or “too much”) will lead to either:1. Disorders associated with defective apoptosis and increased cell survival e.g.i. Cancersii. Autoimmune disorders
2. Disorders associated with increased apoptosis and excessive cell death, e.g.i. Neurodegenerative diseasesii. Ischemic injuryiii. Death of virus-infected cells
With age,Oxidative phosphorylation by mitochondria is reduced, as is synthesis of nucleic acids,proteins etc . Senescent cells have a decreased capacity for uptake of nutrients and for repair of chromosomal damage. There is a steady accumulation of the pigment lipofuscin, which represents a product of lipid peroxidation and evidence of oxidative damage .
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